Anti-viral T cell memory is generated following an initial infection, persists longterm in vivo, and can provide protective immunity to viral challenge. The role of virus-specific memory CDS T cells in protective anti-viral responses has been well-characterized; however, considerably less is known about the function of memory CD4 T cells in anti-viral immunity. Memory CD4 T cells can play multifarious roles in coordinating secondary responses via their direct effector functions, and their ability to "help" or promote cellular and humoral responses. Moreover, memory CD4 T cells also exhibit diverse migration and residence in multiple lymphoid and non-lymphoid tissue sites, although how these different functional and migration properties of memory CD4 T cells function in anti-viral immunity is not known. We have developed a novel mouse model in which anti-influenza immune responses are directed by influenza-specific memory CD4 T cells which has strong clinical relevance given that most adults and older children have been exposed to influenza and retain influenza-specific memory T cells. We found that memory CD4 T cells coordinate secondary responses to influenza challenge manifested by efficient lung viral clearance, along with extensive lung immunopathology and inflammation, and clinical morbidity manifested by weight loss and reduced blood oxygen saturation, revealing a dual nature of memory CD4 T cell anti-viral responses. Our preliminary data further indicate that altering the tissue distribution, homing capacities, and expansion of memory CD4 T cells can shift the balance of protection and immunopathology in secondary responses to influenza virus challenge. We hypothesize that memory CD4 T cell-mediated viral clearance and immunopathology are controlled by distinct memory CD4 T cell-mediated functions that are further regulated by the tissue compartment. To address this hypothesis, our goals are to elucidate the functional mechanisms for anti-viral protection and immunopathology by memory CD4 T cells, incuding the role of direct effector function, chemokine-mediated recruitment and helper functions of memory CD4 T cells in influenza secondary responses. We will also determine the role of tissue-resident memory CD4 T cells in shaping anti-viral secondary responses. Results from the proposed research can lead to the design and implementation of strategies that target memory CD4 T cells, to retain their protective aspects, yet minimize pathological consequences.